title: Modulation of inducible nitric oxide synthase mRNA stability by tetrahydrobiopterin in vascular smooth muscle cells.
abstract: Tetrahydrobiopterin (BH4) regulates inducible nitric oxide synthase (iNOS) as cofactor and allosteric effector. The present paper describes a novel function of BH4 in vascular smooth muscle cells (SMC). By varying BH4 levels with dicumarol (an inhibitor of BH4 synthesis) and sepiapterin (an exogenous source of co-factor), we investigated iNOS expression in activated rat aortic SMC. In sepiapterin-supplemented cells, iNOS protein levels were increased while in dicumarol-treated cells, iNOS levels were diminished. Time-kinetic experiments revealed that inhibition or supplementation of BH4 synthesis had no effects on iNOS induction or transcription rate. However, iNOS mRNA was present over a prolonged time in sepiapterin-supplemented SMC. Analysis of iNOS mRNA levels showed stable iNOS mRNA in sepiapterin-treated cells 8 hours after transcription inhibition, while in dicumarol-treated cells iNOS mRNA disappeared. The decrease of iNOS mRNA by dicumarol was abolished by sepiapterin. These data indicate that BH4 post-transcriptionally stabilizes iNOS mRNA in SMC. By this way BH4 modulates iNOS expression in the vascular system.
authors.affiliation: Department of Medicine, University of Zurich, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Linscheid
authors.forename: A
authors.initials: A
authors.lastname: Schaffner
authors.forename: G
authors.initials: G
authors.lastname: Schoedon
mesh_terms: D000818:Animals; D001483:Base Sequence; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D001728:Dicumarol / Q000494:pharmacology; D004355:Drug Stability; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D016133:Polymerase Chain Reaction; D011621:Pteridines / Q000494:pharmacology; D011622:Pterins; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D051381:Rats
chemical_list: D017931:DNA Primers; D011621:Pteridines; D011622:Pterins; D012333:RNA, Messenger; D001708:Biopterins; D001728:Dicumarol; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C003402:sapropterin